Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that is incurable and untreatable, except symptomatically. Alzheimer's disease affects over 13 million people world-wide. Persons suffering from Alzheimer's disease may have one of two forms of this disease, familial AD or sporadic AD.
Familial Alzheimer's disease is an early-onset disease, generally occurring before the age of fifty, and accounts for only about 5 to 10% of all Alzheimer's cases. Familial AD is inherited and follows conventional patterns of Mendelian inheritance. This form of AD has been linked to nuclear chromosomal abnormalities.
In contrast, the second form of Alzheimer's disease, sporadic AD, is a late-onset disease which is not inherited or caused by nuclear chromosomal abnormalities. This late-onset form of the disease is the more common type of Alzheimer's disease and is believed to account for approximately 90 to 95% of all Alzheimer's cases. The cause of sporadic AD is not known.
It has been recognized that some degenerative diseases, such as Leber's hereditary optic neuropathy (LHON), myoclonic epilepsy lactic acidosis and stroke (MELAS), and myoclonic epilepsy ragged red fiber syndrome (MERRF), are transmitted through mitochondrial DNA defects. Mitochondrial DNA defects have also been implicated in explaining the apparently "sporadic" (nonmendelian) occurrence of some degenerative neurologic disorders, such as Parkinson's and Alzheimer's disease. Since all proteins encoded by the mitochondrial genome are components of the electron transport chain, deficits in electron transport function have been reported in Parkinson's and Alzheimer's disease. Of particular interest, it has been reported that defects in cytochrome c oxidase, an important terminal component of the electron transport chain located in the mitochondria of eukaryotic cells, may be involved in Alzheimer's disease.
Recent findings show that the catalytic activity, but not the physical levels of cytochrome c oxidase (COX), are decreased in the blood of individuals meeting the clinical criteria of probable Alzheimer's disease, or in the brains of patients who died with autopsy-confirmed AD. This suggests that COX is functionally abnormal in AD patients.
One report suggesting a relationship between AD and cytochrome c oxidase is Parker et al., Neurology 40: 1302-1303 (1990), which finds that patients with Alzheimer's disease have reduced cytochrome c oxidase activity. It has also been shown by Bennett et al., J. Geriatric Psychiatry and Neurology 5: 93-101 (1992), that when sodium azide, a specific inhibitor of cytochrome c oxidase was infused into rats, the rats suffered impaired memory and learning (a form of dementia). The rats mimicked the effect of Alzheimer's disease in humans. In addition, the sodium azide-tested rats failed to display long term potentiation, demonstrating loss of neuronal plasticity.
Despite these findings, the exact mechanism producing the electron transport dysfunctions is not known for Alzheimer's disease, nor has a genetic or structural basis for these dysfunctions been identified. Without knowing what causes these electron transport dysfunctions and in particular the genetic or structural basis, it is difficult to diagnose or treat Alzheimer's disease, especially the predominant form, sporadic AD.
To date, the diagnosis of probable Alzheimer's disease is by clinical observation and is a diagnosis of exclusion. A structured clinical approach is used to reduce the diagnostic error rate, but the accuracy of clinical diagnosis is rarely better than 70% to 80% in the hands of the most skilled neurologist, and less accurate when conducted outside specialized centers. Current clinical diagnostic practice is, at best 70%-80% specific. Clinical criteria do not rule out senile dementia of the Lewy Body Variant (SDLDB) (approximately 25% of all AD), a dementia form closely related to sporadic AD. In addition, multi-infarct dementia is very often over-reported. Unfortunately, definitive diagnosis can only be accomplished by pathological examination at autopsy. While attempts have been made to diagnose Alzheimer's disease by identifying differences in certain biological markers, including protease nexin II and apolipoprotein E alleles, this approach has not been successful. Incomplete penetrance in AD patients or crossover into normal or other disease populations makes identification of biological markers an unreliable method of diagnosis. Clearly, a reliable diagnosis of Alzheimer's at its earliest stages is critical for efficient and effective intercession and treatment of this debilitating disease. There exists a definite need for an effective diagnostic of Alzheimer's disease, and especially for the more prevalent form, sporadic AD. There exists a need for a non-invasive diagnostic that is reliable at or before the earliest manifestations of AD symptoms.
Not only does the Alzheimer's field currently lack a reliable, early means of detection, there is at present no effective therapy for AD, other than certain palliative treatments. Current therapies in clinical evaluation are designed to treat the symptoms of the disease and not impact the underlying pathology of AD. These therapies include Cognex, Velnacrine, E2020, and other similar agents known in the field. However, since the primary etiologic events in AD are not yet known in the art, rational therapies have not been designed. There exists a need for effective therapies, particularly those that address the primary cause of AD.
The present invention satisfies these needs for a useful diagnostic test for the risk or presence of Alzheimer's disease and provides related advantages as well.